Genetic Analysis of Retinal Cone Photoreceptor Function

视网膜锥体感光功能的遗传分析

• 批准号: 8629745
• 负责人: Susan E Brockerhoff
• 金额: $ 30.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-13 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629745
• 关键词: Actins; Apical; Architecture; Biological Models; Carrier Proteins; Cells; Cone; Cytology; Cytoskeleton; Data; Defect; Derivation procedure; Equilibrium; Golgi Apparatus; Homeostasis; Investigation; Larva; Lipids; Membrane Protein Traffic; Molecular; Morphology; Nature; Outcome; Phenotype; Phosphatidylinositol Phosphates; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Photoreceptors; Phototransduction; Process; Protein Biosynthesis; Proteins; Regulation; Research Personnel; Retinal Cone; Role; Seminal; Series; Signal Transduction; Sorting - Cell Movement; Structure; Synapses; Synaptic Vesicles; Testing; Vesicle; Work; Zebrafish; cell type; density; genetic analysis; mutant; novel; polyphosphoinositide phosphatase; research study; ribbon synapse; synaptojanin

Photoreceptors are highly polarized, compartmentalized cells. Protein synthesis initiates in the inner segment and then transport proceeds in the apical direction toward the outer segment or basally toward the synapse. In recent years, several investigators have made seminal discoveries about the mechanism(s) of transport to the outer segment. In contrast, very little is known about the transport of proteins destined for the synapse or the sorting within the inner segment of proteins destined for different cellular compartments. Phosphoinositides are known to be key regulators in membrane trafficking and are involved in signaling, specification and protein recruitment in a wide variety of cell types. A key regulator of cellular phosphoinositides is the lipid phosphatase, synaptojanin I (SynJ1), whose primary intracellular target is PI(4,5)P2. We have established zebrafish as a model system in which to evaluate both phosphoinositide signaling and SynJ1 function in the process of protein sorting in cone photoreceptors. Our current work finds a role for SynJ1 in the inner segment. We find that SynJ1 concentrates in the cone inner segment and that large vesicles abnormally accrue and/or the Golgi architecture is disrupted in nrc mutants lacking this protein. We hypothesize that the inner segment phenotype reflects a disruption of transport and sorting of proteins destined for the synapse. We propose a series of experiments that test this hypothesis and define precisely the abnormal vesicular structures we detect in nrc inner segments, their content and derivation. The specific expected outcome of our proposal is a detailed understanding of the inner segment defect detected in nrc when the balance of polyphosphoinositides within the photoreceptor is disrupted due to the loss of the critical PI(4,5)P2 phosphatase, SynJ1. In addition, our studies will provide fundamental information about the cellular distribution of polyphosphoinositides in both wild-type and nrc cone photoreceptors. Finally, our studies will define the importance of different structural domains of SynJ1. The critical, fundamental information we discover from the studies outlined in this proposal will help open this field to many additional important investigations.

光感受器是高度极化、区隔化的细胞。蛋白质合成开始于内段